Association of Single-Nucleotide Variants in the Human Leukocyte Antigen and Other Loci With Childhood Hodgkin Lymphoma
Authors: Cheng Chen, Nan Song, Qian Dong, Xiaojun Sun, Heather L. Mulder, John Easton, Jinghui Zhang, Yutaka Yasui, Smita Bhatia, Gregory T. Armstrong, Hui Wang, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Studies focusing on genetic susceptibility of childhood Hodgkin lymphoma (HL) are limited. <h3>Objectives</h3> To identify genetic variants associated with childhood-onset HL vs adult-onset HL. <h3>Design, Setting, and Participants</h3> This genetic association study was performed with 3 cohorts: the St Jude Lifetime Cohort Study (SJLIFE), initiated in 2007 with ongoing follow-up, and the original and expansion cohorts of the Childhood Cancer Survivor Study (CCSS), initiated in the 1990s with ongoing follow-up. Results of these genome-wide association studies (GWASs) were combined via meta-analysis. Data were analyzed from June 2021 to June 2022. <h3>Main Outcomes and Measures</h3> Childhood HL was the focused outcome. Single-nucleotide variant (SNV, formerly single-nucleotide polymorphism) array genotyping and imputation were conducted for the CCSS original cohort, and whole-genome sequencing was performed for the SJLIFE and CCSS expansion cohort. <h3>Results</h3> A total of 1286 HL cases (mean diagnosis [SD] age, 14.6 [3.9] years), 6193 non-HL childhood cancer cases, and 369 noncancer controls, all of European ancestry, were included in the analysis. Using step-wise conditional logistic regression, the odds ratios (ORs) for each of the 3 independent SNVs identified in the human leukocyte antigen (HLA) locus were 1.80 (95% CI, 1.59-2.03;<i>P</i> = 2.14 × 10<sup>−21</sup>) for rs28383311, 1.53 (95% CI, 1.37-1.70;<i>P</i> = 2.05 × 10<sup>−14</sup>) for rs3129198, and 1.51 (95% CI, 1.35-1.69;<i>P</i> = 6.21 × 10<sup>−13</sup>) for rs3129890. Further HLA imputation revealed 9 alleles and 55 amino acid changes that potentially conferred HL susceptibility. In addition, 5 non-HLA loci were identified: (1) rs1432297 (OR, 1.29; 95% CI, 1.18-1.41;<i>P</i> = 2.5 × 10<sup>−8</sup>;<i>r</i><sup>2</sup> = 0.55; D′ = 0.75 with previously reported rs1432295,<i>REL</i>); (2) rs2757647 (OR, 1.30; 95% CI, 1.18-1.42;<i>P</i> = 3.5 × 10<sup>−8</sup>;<i>r</i><sup>2</sup> = 0.59; D′ = 0.83 with previously reported rs6928977,<i>AHI1</i>); (3) rs13279159 (OR, 1.33; 95% CI, 1.20-1.47;<i>P</i> = 1.7 × 10<sup>−8</sup>;<i>r</i><sup>2</sup> = 0.75; D′ = 1.00 with previously reported rs2019960,<i>PVT1</i>); (4) rs3824662 (OR, 1.52; 95% CI, 1.33-1.73;<i>P</i> = 3.9 × 10<sup>−10</sup>;<i>r</i><sup>2</sup> = 0.91; D′ = 1.00 with previously reported rs3781093,<i>GATA3</i>); and (5) rs117953624 (OR, 1.98; 95% CI, 1.56-2.51;<i>P</i> = 1.5 × 10<sup>−8</sup>; minor allele frequency, 0.02), a novel uncommon SNV mapped to<i>PDGFD</i>. Twelve of 18 previously reported genome-wide significant non-HLA SNVs (67%) were replicated with statistically significant results. <h3>Conclusions and Relevance</h3> In this genetic association study, a predominantly common and potentially unique genetic etiology was found between childhood-onset and adulthood-onset HL.